This K08 Mentored Clinical Scientist Development Award proposes to provide advanced research training in the genetics of fear and anxiety disorders for Dr. John M. Hettema, M.D., Ph.D. Dr. Kenneth S. Kendler, M.D., a world renowned researcher in psychiatric genetics, will serve as Dr. Hettema's primary sponsor. The training will take place at the Virginia Institute for Psychiatric and Behavioral Genetics of Virginia Commonwealth University, which provides a rich, stimulating environment for the conduct of training and research. Dr. Hettema proposes to receive training in epidemiology, statistical and molecular genetics, and experimental methods for measuring anxiety-related traits, including psychophysiology and neuroimaging. Specific research objectives include i) examining the stability, reliability, and heritability of self-report measures in anxiety disorders using a longitudinal design; ii) determine the extent to which the high comorbidity observed between the anxiety disorders is determined by genetic and environmental factors shared between them, including specific individual risk factors such as gender, early enviroment, stressful life events, etc.; iii) determine the genetic correlations between neuroticism and the anxiety disorders and the causal relations between them; iv) elucidate the genetic and environmental factors underlying the increased risk for major depression caused by pre-existing anxiety disorders and what effects gender has on this relationship; v) understand the genetic structure of fear conditioning in humans and to what extent this is shared with phobias. In addition, Dr. Hettema intends to apply knowledge gained in training to design pilot studies that incorporate experimentally derived anxiety-related measures from a genetically informative sample of twins from the Virginia Twin Registry, combining this data with the existing database of self-report anxiety measures. This research training plan will allow Dr. Hettema to emerge at the end of the proposal period as an independent researcher in the genetics of anxiety disorders, seeking to extend this work further by combining self-report and experimentally derived anxiety-related measures with linkage and association studies to identify genetic loci and brain mechanisms involved in the anxiety disorders.